Expression of transforming growth factor alpha and epidermal growth factor receptor in adult polycystic kidney disease

Abstract

Adult polycystic kidney disease (APKD) is a common genetic disease with a frequency of 1:1000. Evidence suggests that transforming growth factor alpha (TGFα) signaling may contribute to the hyperproliferation of the cystic epithelia in APKD. TGFα and epidermal growth factor (EGF) are well known mitogens expressed in the kidney and both exert their biological activities through binding to the same EGF receptor. A transgenic mouse that over-expressed TGFα developed renal cysts; raised levels of TGFα and EGF receptor mRNA were found in kidneys from two autosomal dominant APKD patients. To study the role of TGFα in cyst formation, we analyzed nine anatomically diagnosed adult polycystic kidneys and four normal kidneys using immunohistochemistry. We also traced the possible origins of the cysts by staining with the proximal convoluted tubule (PCT) marker, gp330, and the distal convoluted tubule (DCT) and collecting tubule (CT) marker, peanut agglutinin (PNA). In normal kidneys, TGFα protein was concentrated in the DCT and CT and EGF receptor protein in all three tubule types. In the early cysts of APKD, the cystic epithelia showed strong positive staining with TGFα, EGF receptor and gp330 but negative with PNA. Strong TGFα and EGF receptor staining was also found in the mixture of advanced cysts in the end- stage cystic kidneys although the cysts are likely to be derived from different segments of the renal tubules. This increased TGFα and EGF receptor expression in all cases and all types of cysts suggests that autocrine/paracrine stimulation by TGFα may be a common mechanism in cyst development in APKD.